Cardiovascular disease is the leading cause of death in women in Western countries. Despite preventive strategies, in the past decades the incidence of cardiovascular events has shown a decline in men but a rise in women, matching the growth of the population of postmenopausal women. Several epidemiological findings suggest the causative pathophysiological role of ovarian hormone deficiency in the development of cardiovascular disease in women. Observational and randomized studies have suggested that hormone replacement therapy in early postmenopause could be beneficial from a cardiovascular point of view. Conversely, aging, time since menopause and presence of cardiovascular risk factors or cardiovascular disease may decrease its efficacy and increase the risk of cardiovascular events. It is plausible that the unfavorable effects of the estrogen/progestin combination used in the randomized studies are not related to the hormone preparation per se but rather to the use of hormones in the less receptive group of women, older and with cardiovascular risk factors. Clinical judgment, choice of the right dose and estrogen/progestin combination are of pivotal importance to maximize the beneficial effect of estrogen replacement therapy/hormone replacement therapy, especially if given within a reasonable time after the menopause to women who need the therapy for the relief of menopausal symptoms.